Our laboratory studies a group of rare genetic disorders due to inborn errors of cholesterol synthesis or impaired lysosomal functioning. These disorders include Smith-Lemli-Opitz syndrome, Juvenile Batten disease (CLN3 disease) and Niemann-Pick disease, type C. SLOS is a human autosomal recessive multiple congenital anomaly/cognitive impairment syndrome characterized by facial dysmorphology, cognitive impairment, a characteristic behavioral phenotype, growth retardation, and variable structural anomalies of the heart, lungs, brain, gastrointestinal tract, limbs, genitalia and kidneys. SLOS also has a distinct behavioral phenotype which includes self-injurious and autistic features. Biochemically, patients with SLOS have an inborn error of cholesterol biosynthesis; specifically, they have a defect in the conversion of 7-dehydrocholesterol to cholesterol. However, we do not know why these children have such a variety of congenital malformations, and neurological problems. Our laboratory is using various model systems including mouse, zebrafish, and iPS cells to further our understanding of how the malformations seen in this syndrome develop, and to further our understanding of the neurophysiological basis of the neurological problems associated with this syndrome. Various biochemical, molecular, and proteomic approaches are being utilized to investigate these issues. In addition to being used to understand the pathophysiological processes underlying SLOS, we are using these model systems to develop and test potential therapeutic interventions. One of the most intriguing aspects of SLOS is the distinct behavioral phenotype. Most patients with SLOS have autistic features. We are currently working in collaboration with groups from Kennedy Krieger Institute in Baltimore and NIMH to further analyze this association. Our laboratory investigations of SLOS are complemented by a clinical research effort and we have seen over 100 patients with SLOS. In addition to SLOS, we have developed mouse models of lathosterolosis, desmosterolosis, and HEM dysplasia. These human syndromes all involve defects in cholesterol synthesis. We are using these mouse models to further our understanding of the biological processes which cause the birth defects found in these syndromes. Our laboratory also works to understand the pathological processes underlying Niemann-Pick disease, type C1 (NPC1). NPC1 is a genetic disorder due to impaired intracellular cholesterol and lipid transport. Patients with NPC1 die due to a progressive neurological disorder. The laboratory is applying proteomic techniques to understand pathophysiological processes underlying clinical problems found in NPC and to identify biomarkers that can be used in future clinical trials. Recently we have also begun to work on another lysosomal storage disease caused by mutation of CLN3 resulting in Juvenile Batten disease. Similar to NPC1, CLN3 is a neurodegenerative disorder primarily affecting children. The basic science work done in this laboratory supports and complements the clinical work also being performed by this Section. The combination of basic science and clinical science work in one Section facilitates the rapid translation of findings from the bench to the bedside and vice versa.